Journal of Medicinal Chemistry
Article
3.57 (2, 2H), 3.33−3.29 (m, 2H), 3.21−3.13 (m, 1H), 3.04 (dd, J =
13.0, 6.7 Hz, 2H), 2.99−2.92 (m, 1H), 2.82−2.76 (m, 2H), 2.67−
2.62 (m, 2H), 2.49 (s, 3H), 2.44 (t, J = 7.3 Hz, 2H), 1.56−1.43 (m,
6H), 1.36−1.28 (m, 6H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ =
167.5 (1C), 154.8 (1C), 145.1 (1C), 144.2 (1C), 135.9 (1C), 134.2
(1C), 133.8 (1C), 128.7 (1C), 128.3 (2C), 128.2 (1C), 127.4 (1C),
126.5 (1C), 125.9 (1C), 125.7 (1C), 125.4 (2C), 125.3 (1C), 120.3
(1C), 119.8 (1C), 119.5 (1C), 75.8 (1C), 57.8 (1C), 55.5 (1C), 55.1
(1C), 50.5 (1C), 47.1 (1C), 40.5 (1C), 37.8 (1C), 29.2 (1C), 28.7
(1C), 27.8 (1C), 26.6 (1C), 26.5 (1C), 26.2 (1C), 25.8 (1C), 24.9
(1C) ppm. MS(ESI): [M + H]+ calc. for C35H44N4O2H = 553.36;
found 553.20; HPLC (method A): tR = 10.00 min, purity = 98.5%.
13-Methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-yl-{10-[3,4-dihydroisoquinolin-2(1H)-yl]decyl}-
carbamate (19l). Following GP7, 13-methyl-5,8,13,13a-tetrahydro-
6H-isoquinolino[1,2-b]quinazolin-10-ol 13 (14 mg, 53 μmol, 1.4
equiv), NaH (60%, 4 mg, 92 μmol, 2.5 equiv), and 4-nitrophenyl-{10-
[3,4-dihydroquinolin-1(2H)-yl]decyl}carbamate 18l (17 mg, 37
μmol, 1 equiv) were applied to obtain 13-methyl-5,8,13,13a-
tetrahydro-6H-isoquinolino[1,2-b]quinazolin-10-yl0{10-[3,4-dihy-
droisoquinolin-2(1H)-yl]decyl}carbamate 19l (9 mg, 16 μmol, 42%)
as a colorless oil after column chromatography (CH2Cl2/MeOH =
95/5, Rf = 0.33).
carbamate 19n (98 mg, 0.21 mmol, 78%) as a yellow oil after column
chromatography (CH2Cl2/MeOH = 95/5, Rf = 0.20).
1H-NMR (400 MHz, CDCl3): δ = 7.49 (s, 1H), 7.40−7.36 (m,
1H), 7.24−7.20 (m, 2H), 7.17−7.13 (m, 1H), 7.08 (s, 1H), 6.94−
6.92 (m, 1H), 6.92−6.88 (m, 2H), 6.78−6.75 (m, 1H), 4.84 (s, 1H),
4.08−3.85 (m, 4H), 3.31−3.20 (m, 3H), 3.14−3.04 (m, 1H), 2.84
(dt, 1H, J = 4.71, 16.16 Hz), 2.76−2.69 (m, 1H), 2.57 (s, 3H), 1.81
(dt, 2H, J = 7.22, 14.34 Hz), 1.56 (dt, 2H, J = 7.04, 14.41 Hz), 1.40−
1.32 (m, 4H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 168.2 (1C),
153.5 (1C), 146.0 (1C), 137.1 (1C), 136.1 (1C), 134.1 (1C), 129.3
(1C), 129.0 (1C), 128.9 (1C), 127.6 (1C), 126.0 (1C), 125.9 (1C),
125.4 (1C), 120.4 (1C), 120.1 (1C), 119.7 (1C), 56.3 (1C), 47.9
(1C), 47.2 (1C), 38.0 (1C), 36.6 (1C), 31.1 (1C), 29.8 (1C), 28.7
(1C), 26.4 (1C), 26.3 (1C) ppm. MS(ESI): [M + 2H]2+ calc. for
C27H33N5O2H2 = 230.64; found 230.70; HPLC (method A): tR
=
6.80 min, purity = 96.3%.
13-Methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-yl-[6-(pyrrolidin-1-yl)hexyl]carbamate (19o). Follow-
ing GP7, 13-methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-ol 13 (63 mg, 0.24 mmol, 1 equiv), NaH (60%, 6.4
mg, 0.27 mmol, 1.1 equiv), and 18o (100 mg, 0.30 mmol, 1.25 equiv)
were applied to obtain 13-methyl-5,8,13,13a-tetrahydro-6H-
isoquinolino[1,2-b]quinazolin-10-yl-[6-(pyrrolidin-1-yl)hexyl]-
carbamate 19o (77 mg, 0.17 mmol, 71%) as a yellow oil after column
chromatography (CH2Cl2/MeOH = 95/5, Rf = 0.19).
1H-NMR (400 MHz, CDCl3): δ = 7.49−7.45 (m, 1H), 7.40−7.36
(m, 1H), 7.24−7.20 (m, 2H), 7.16−7.104 (m, 4H), 7.04−7.00 (m,
1H), 6.91−6.84 (m, 1H), 6.79−6.76 (m, 1H), 6.65−6.61 (m, 1H),
4.71 (s, 1H), 3.80 (q, J = 15.9 Hz, 2H), 3.53−3.47 (m, 2H), 3.33−
3.29 (m, 2H), 3.25−3.19 (m, 1H), 3.09 (dd, J = 13.0, 6.7 Hz, 2H),
2.99−2.92 (m, 1H), 2.85−2.70 (m, 4H), 2.69−2.65 (m, 2H), 2.48 (s,
3H), 2.40−2.36 (m, 2H), 1.60−1.45 (m, 4H), 1.38−1.29 (m, 6H)
ppm. 13C-NMR (100 MHz, CDCl3): δ = 167.7 (1C), 154.9 (1C),
145.2 (1C), 144.0 (1C), 135.7 (1C), 134.3 (1C), 133.8 (1C), 128.8
(1C), 128.7 (1C), 128.4 (1C), 127.5 (1C), 126.6 (1C), 126.2 (1C),
126.0 (1C), 125.8 (1C), 125.2 (1C), 122.9 (1C), 120.3 (1C), 119.6
(1C), 58.4 (1C), 56.8 (1C), 55.9 (1C), 50.8 (1C), 48.9 (1C), 38.8
(1C), 37.8 (1C), 29.8 (1C), 29.5 (1C), 29.5 (1C), 29.2 (1C), 28.8
(1C), 28.7 (1C), 28.6 (1C), 27.6 (1C), 26.9 (1C) ppm. MS(ESI): [M
+ H]+ calc. for C37H48N4O2H = 581.39; found 581.25; HPLC
(method A): tR = 10.36 min, purity = 99.9%.
13-Methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-yl-{6-[1H-benzo[d]imidazol-1-yl]hexyl}carbamate
(19m). Following GP7, 13-methyl-5,8,13,13a-tetrahydro-6H-
isoquinolino[1,2-b]quinazolin-10-ol 13 (61 mg, 0.23 mmol, 1
equiv), NaH (60%, 6 mg, 0.26 mmol, 1.1 equiv), and 18m (110
mg, 0.29 mmol, 1.26 equiv) were used to obtain 13-methyl-
5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]quinazolin-10-yl-{6-
[1H-benzo[d]imidazol-1-yl]hexyl}carbamate (19m) (53 mg, 0.1
mmol, 45%) as a yellow oil after column chromatography
(CH2Cl2/MeOH = 95/5, Rf = 0.29).
1H-NMR (400 MHz, CDCl3): δ = 7.39−7.33 (m, 1H), 7.25−7.20
(m, 2H), 7.19−7.12 (m, 1H), 6.94−6.89 (m, 2H), 6.81−6.75 (m,
1H), 4.94 (s, 1H), 4.16−3.91 (m, 2H), 3.87−3.73 (m, 2H), 3.28−
3.23 (m, 2H), 2.96−2.76 (m, 4H), 2.64 (s, 3H), 1.98−1.88 (m, 4H),
1.63−1.53 (m, 4H), 1.50−1.37 (m, 4H) ppm. 13C-NMR (100 MHz,
CDCl3): δ = 168.2 (1C), 132.8, 129.0, 128.7, 127.9, 126.2, 119.8
(1C), 55.5 (1C), 53.8 (2C), 53.6 (1C), 48.0 (1C), 40.9 (1C), 29.5
(1C), 26.3 (1C), 25.9 (1C), 25.5 (1C), 23.5 (2C) ppm. MS(ESI): [M
+ 2H]2+ calc. for C28H38N4O2H2 = 232.16; found 232.15; HPLC
(method A): tR = 6.66 min, purity = 95.4%.
13-Methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-yl-[6-(piperidin-1-yl)hexyl]carbamate (19p). Follow-
ing GP7, 13-methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-ol 13 (39 mg, 0.147 mmol, 1 equiv), NaH (60%, 3.9
mg, 0.163 mmol, 1.1 equiv), and 18p (57 mg, 0.163 mmol, 1.1 equiv)
were used to obtain 13-methyl-5,8,13,13a-tetrahydro-6H-
isoquinolino[1,2-b]quinazolin-10-yl-[6-(piperidin-1-yl)hexyl]-
carbamate 19p (30 mg, 0.063 mmol, 43%) as a brown oil after
column chromatography (CH2Cl2/MeOH = 95/5, Rf = 0.10).
1H-NMR (400 MHz, CDCl3): δ = 7.39−7.35 (m, 1H), 7.24−7.20
(m, 2H), 7.17−7.13 (m, 1H), 6.91−6.88 (m, 2H), 6.80−7.76 (m,
1H), 4.83 (s, 1H), 4.03 (d, 1H, J = 15.70 Hz), 3.89 (d, 1H, J = 15.72
Hz), 3.67−3.59 (m, 2H), 3.31−3.19 (m, 3H), 3.15−3.03 (m, 1H),
2.83 (dt, 1H, J = 4.76, 16.25 Hz), 2.77−2.69 (m, 1H), 2.57 (s, 3H),
2.34 (t, 4H, J = 6.73 Hz), 1.87 (dt, 4H, J = 5.86, 12.72 Hz), 1.77−1.67
(m, 2H), 1.64−1.56 (m, 4H), 1.47−1.38 (m, 4H) ppm. MS(ESI): [M
+ H]+ calc. for C29H40N4O2H = 477.33; found 477.20; HPLC
(method A): tR = 6.91 min, purity = 98.1%.
1H-NMR (400 MHz, CDCl3): δ = 7.93 (s, 1H), 7.84−7.80 (m, 1H,
arom.), 7.42−7.36 (m, 2H), 7.33−7.29 (m, 2H), 7.23−7.20 (m, 2H),
7.17−7.13 (m, 1H, arom.), 6.90−6.86 (m, 2H), 6.77−6.75 (m, 1H),
4.85 (s, 1H), 4.21−4.15 (m, 2H), 4.08−3.84 (m, 2H), 3.23−3.18 (m,
3H, CH2), 3.14−3.04 (m, 1H), 2.84 (dt, 1H, J = 4.75, 16.06 Hz),
2.77−2.69 (m, 1H), 2.58 (s, 3H), 1.95−1.88 (m, 2H), 1.60−1.50 (m,
2H), 1.42−1.34 (m, 4H) ppm. 13C-NMR (100 MHz, CDCl3): δ =
168.1 (1C), 155.4 (1C), 144.3 (1C), 143.0 (1C), 136.1 (1C), 134.0
(1C), 129.0 (1C), 128.9 (1C), 127.7 (1C), 125.9 (1C), 125.3 (1C),
123.1 (1C), 122.3 (1C), 120.9 (1C), 119.7 (1C), 109.8 (1C), 101.7
(1C), 56.2 (1C), 47.9 (1C), 45.2 (1C), 42.9 (1C), 41.1 (1C), 38.0
(1C), 29.9 (1C), 28.6 (1C), 26.6 (1C), 26.4 (1C) ppm. MS(ESI): [M
+ H]+ calc. for C31H35N5O2H = 510.29, found 510.15; HPLC
(method A): tR = 8.02 min, purity = 97.5%.
13-Methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]-
quinazolin-10-yl-[6-(1H-imidazol-1-yl)hexyl]carbamate (19n). Fol-
lowing GP7, 13-methyl-5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-
b]quinazolin-10-ol 13 (71 mg, 0.27 mmol, 1 equiv), NaH (60%, 7.2
mg, 0.30 mmol, 1.1 equiv), and 18n (110 mg, 0.33 mmol, 1.2 equiv)
were used to obtain 13-methyl-5,8,13,13a-tetrahydro-6H-
isoquinolino[1,2-b]quinazolin-10-yl-[6-(1H-imidazol-1-yl)hexyl]-
tert-Butyl-4-[6-({[(13-methyl-5,8,13,13a-tetrahydro-6H-
isoquinolino[1,2-b]quinazolin-10-yl)oxy]carbonyl}amino)hexyl]-
piperazine-1-carboxylate (19q). Following GP7, 13-methyl-
5,8,13,13a-tetrahydro-6H-isoquinolino[1,2-b]quinazolin-10-ol 13 (47
mg, 0.178 mmol, 1 equiv), NaH (60%, 4.8 mg, 0.2 mmol, 1.1 equiv),
and 18q (100 mg, 0.222 mmol, 1.25 equiv) were applied to obtain
tert-butyl-4-[6-({[(13-methyl-5,8,13,13a-tetrahydro-6H-isoquinolino-
[1,2-b]quinazolin-10-yl)oxy]carbonyl}amino)hexyl]piperazine-1-car-
boxylate 19q (91 mg, 0.158 mmol, 89%) as a yellow oil after column
chromatography (CH2Cl2/MeOH = 96/4, Rf = 0.23).
1H-NMR (400 MHz, CDCl3): δ = 7.41−7.36 (m, 1H), 7.24−7.19
(m, 2H), 7.17−7.13 (m, 1H), 6.92−6.87 (m, 2H), 6.79−6.75 (m,
1H), 4.83 (s, 1H), 4.03 (d, 1H, J = 15.51 Hz), 3.88 (d, 1H, J = 15.90
Hz), 3.50−3.42 (m, 4H), 3.31−3.21 (m, 3H), 3.14−3.02 (m, 1H),
2.89−2.79 (m, 1H), 2.77−2.67 (m, 1H), 2.57 (s, 3H), 2.45−2.31 (m,
6H), 1.60−1.50 (m, 4H), 1.46 (s, 9H), 1.40−1.33 (m, 4H) ppm. 13C-
NMR (100 MHz, CDCl3): δ = 155.3 (1C), 154.9 (1C), 145.9 (1C),
S
J. Med. Chem. XXXX, XXX, XXX−XXX